Inhibition of indoleamine 2,3-dioxygenase suppresses NK cell activity and accelerates tumor growth.
Inhibition of indoleamine 2,3-dioxygenase suppresses NK cell activity and accelerates tumor growth.
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DOI：
10.1111/j.1533-869x.2003.01108.x
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发表时间：
2003-11-01
影响因子：
--
通讯作者：
Kitano, Seigo
中科院分区：
文献类型：
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作者：
Kai, Seiichiro;Goto, Shigeru;Kitano, Seigo
吲哚胺2，3-双加氧酶(IDO)是一种色氨酸分解代谢酶，在病毒和细菌感染、同种异体移植排斥反应、脑缺血和肿瘤生长等多种病理条件下均有表达。我们曾报道在一些临床病例中IDO mRNA的表达增加，其中IDO阳性患者的无复发生存率明显高于肿瘤中未诱导IDO mRNA的患者。此外，免疫组织化学显示，IDO在肿瘤中的表达不是定位于肿瘤细胞，而是定位于肿瘤浸润性细胞。为了阐明IDO的抗肿瘤作用机制，我们研究了IDO抑制剂(1-甲基-dl-色氨酸，1mT)对小鼠皮下B16肿瘤生长的影响。随后，在体内和体外抑制IDO活性的条件下，研究自然杀伤(NK)细胞的活性。逆转录-聚合酶链式反应检测B16细胞、B16皮下肿瘤、小鼠脾细胞和人NK细胞中IDO基因的表达。观察IDO抑制前后B16皮下肿瘤的生长情况，并在体内、外抑制IDO活性的条件下检测NK细胞的细胞毒活性。在B16皮下肿瘤、荷瘤小鼠脾细胞、与B16共培养的脾细胞和人NK细胞中均有IDO mRNA的表达。第14天，注射B16黑色素瘤细胞后，IDO抑制组小鼠的肿瘤体积明显大于对照组。体内抑制IDO可降低小鼠NK细胞的杀伤活性。体外抑制IDO、NK活性呈1mT剂量依赖性降低。综上所述，这些结果表明IDO通过调节NK细胞的细胞毒活性在抗肿瘤免疫中发挥重要作用。
Indoleamine 2,3-dioxygenase (IDO), a tryptophan catabolizing enzyme, is induced under various pathological conditions, including viral and bacterial infection, allograft rejection, cerebral ischemia, and tumor growth. We have previously reported that the expression of IDO mRNA was increased in some clinical cases of hepatocellular carcinoma in which the recurrence-free survival rate in these IDO-positive patients was significantly higher than that in patients without IDO mRNA induction in tumors. Additionally, IDO expressed in tumors was localized not to the tumor cells but instead to tumor-infiltrating cells by immunohistochemistry. In this study, in order to elucidate the mechanisms underlying anti-tumor effect of IDO, we investigated whether IDO inhibitor (1-methyl-dl-tryptophan, 1MT) affects the growth of subcutaneous B16 tumors in mice. Subsequently, the activity of natural killer (NK) cells was investigated under the conditions of inhibited IDO activity in vivo and in vitro. IDO mRNA expression of B16 cells, B16 subcutaneous tumor, sprenocytes of mice, and human NK cells were studied by reverse transcription-polymerase chain reaction. B16 subcutaneous tumor growth with or without IDO inhibition was observed and cytotoxic activity of NK cells were investigated under the conditions of inhibited IDO activity in vivo and in vitro. IDO mRNA was expressed in B16 subcutaneous tumor, splenocytes of tumor bearing mice, co-cultured splenocytes with B16, and human NK cells. On day 14, after injection of B16 melanoma cells, the sizes of tumors in IDO-inhibited mice were significantly larger than those in control mice. The cytotoxic activity of mice NK cells was reduced by IDO inhibition in vivo. In vitro inhibition of IDO, NK activity was reduced in dose-dependent manner of 1MT. In conclusion, these results indicated that IDO plays an important role in anti-tumor immunity by regulating cytotoxic activity of NK cells.